Food allergy affects approximately 5% of individuals in the USA. The most severe form of food allergy, food-induced anaphylaxis causes approximately 100 deaths per year. An essential question in the food allergy field is to understand the molecular mechanisms that predispose to food allergy and anaphylaxis. In preliminary analysis, employing IL-9 deficient mice, intestinal IL-9 transgenic mice and experimental models of food allergy (intestinal anaphylaxis) we have demonstrated that IL-9 profoundly increases intestinal mast cells, intestinal permeability and predisposes to food allergy. The objective of this application is to define the molecular mechanisms involved in IL-9-mediated predisposition to intestinal anaphylaxis. The working hypothesis of this proposal is that IL-9 is a stimulus and required for the induction of experimental intestinal anaphylaxis. The central hypothesis will be addressed in three aims. In Aim 1, we will employ IL-9-deficient, IL-9R-deficient and WT mice and our experimental model of intestinal anaphylaxis to define the role of IL-9 in the immunopathology of intestinal anaphylaxis. In Aim 2, we will delineate the relationship between IL-9 overexpression in the gastrointestinal tract, intestinal permeability and predisposition to oral antigen sensitization. In Aim 3, we will define the role of mast cells and platelet activating factor in IL-9-induced altered intestinal permeability. We expect to find that IL-9 is central to the regulation of different components of the intestinal inflammatory response and the predisposition to oral antigen-induced intestinal anaphylaxis. Such results will have an important positive impact on human health, as identification of the molecular processes involved in food allergen sensitization and anaphylaxis will provide new and innovative approaches for the specific prevention and treatment of these diseases.Narrative: Food allergy and anaphylaxis are of increasing importance in the western world. Our hypothesis is that the cytokine IL-9 selectively stimulates mast cell- dependent pathways and promotes oral antigen sensitization and the onset of food allergy. Defining the biological processes involved in food allergy susceptibility will advance our understanding of these complex and poorly understood clinical events, and be applicable to the prevention/treatment of other allergic disorders such as eczema and asthma.